SIMPÓSIO SATÉLITE AMGEN
O Papel da Imunoterapia na Otimização dos Desfechos em LLA
• Otimizando os desfechos pós-transplante em LLA Dr. Peter Bader
• Imunoterapia com Blinatumomabe – quais as possibilidades? Dr. Peter Bader
• Discussão de Caso Clínico Dr. Nelson Hamerschlak
Optimizing transplant outcomes in ALL
Peter Bader
SBTMO 2018 – ALL Satellite Symposium
“Role of MRD and Immunotherapy in Optimizing ALL Treatment Outcomes”
Rio de Janeiro, August 2nd, 2018
3
Objectives
• Risk stratifications before transplant and post transplant based on MRD
• Correlation of MRD status pre-HSCT to outcome
• Relapse major cause for treatment failure
• Brief overview of options to prevent relapse in ALL patients
Cellular therapies
Checkpoint inhibitors
Antibody treatment
4
Stem-Cell Transplantation in Children With Acute Lymphoblastic Leukemia: A Prospective
International Multicenter Trial Comparing Sibling Donors With Matched Unrelated Donors—
The ALL-SCT-BFM-2003 TrialChristina Peters, Martin Schrappe, Arend von Stackelberg, André Schrauder, Peter Bader, Wolfram Ebell,Peter Lang, Karl-Walter Sykora,
Johanna Schrum, Bernhard Kremens, Karoline Ehlert, Michael H. Albert,Roland Meisel, Susanne Matthes-Martin, Tayfun Gungor, Wolfgang
Holter, Brigitte Strahm, Bernd Gruhn,Ansgar Schulz, Wilhelm Woessmann, Ulrike Poetschger, Martin Zimmermann, and Thomas Klingebiel
C. Peters et al.
J Clin Oncol 2015
MSD: 71%
MUD: 69%
MSD: 3%
MUD: 10%MSD: 24%
MUD: 22%
MSD: 79%
MUD: 73%
5
M. Kuhlen et al.
Br J Haematol 2017
Outcome of relapse after allogeneic HSCT in children
with ALL enrolled in the ALL‐SCT 2003/2007 trial
6
Risk Stratification Post-transplant• Relapse is the major cause of treatment
failure
Incidence of relapse: 30-60%
• Curative treatment options are limited
• Treatment of impending relapse?MRD
Chimerism
7
Studies on Chimerism in ALL1999-2003
AuthorNumber
ofpatients
DiagnosisInterval of
investigationsMethods
Relapses
Ferandez-Aviles
Leukemia 2003 40 AL, CMLDay 28, monthly
STRMC associated with
rejection and relapse
Barrios et al.
Haematologica2003
133 ALL, AML monthly STR
In-MC associatedwith relapse in uni and multivariate
analysis
Guimond et al
BR J Haemoalogy
2000
81Leukemia, Lymphoma,
MDSNot specified STR
MC associated with relapse
in children: yes
In adults: no
Schaap
Leukemia 200219/231
AL and othermalignancies
Two times Cytogen. No association
8
Consequences?Role for Pre-emptive Imunotherapy?
T-cells ChimerismRelapse
CC
AR
MC
Donor T-cells
Recipient T-cells
Immunotherapy by
withdrawal of
immunosuppression
or DLI
9
responded to immunotherapy but died of severe infection
with multiple-organ involvement). The third patient did
not respond to low-dose DLI and progressed to frank he-
matological relapse. Two additional DLIs with increasing
cell doses(up to5 106) weregiven. Thepatient’sleukemic
blast cellsdisappeared, and completedonor chimerism was
restored; however, the patient died on day 323 of severe
acuteGVHD of theskin, liver, and intestines.
DISCUSSION
Despite the completion of several studies, the efficacy of
immunotherapy after allogeneic transplantation for acute
leukemia isstill thesubject of debate.6-9,18,37
Theresultsreported heredemonstratethat serial char-
acterization of posttransplantation chimerism offers the
possibility of identifying those patients who are at highest
risk to develop relapse. Moreover, these results show that
many patients with increasing MC, who otherwise face
almost certain relapse and death, can be rescued by addi-
tional immunotherapy. The probability of 3-year EFS in
patientswith increasingMCwas0%in theuntreated group,
but 37% in patients who received early treatment. We ac-
knowledgethat becausethisstudy wasnot randomized, we
cannot rule out selection bias as a factor in our results.
However, the striking difference between the outcomes of
treated and untreated patientsislikely to reflect theeffect of
therapy, as the two groups of patients with increasing MC
with or without prophylactic therapy did not differ with
regard to relevant transplant factorssuch asdonor, typeof
graft, conditioning regimen, or T-cell depletion of thegraft.
A GVL reaction in patientswith ALL issuggested bythe
higher incidenceof relapsein theabsenceof GVHD38-40or
with the use of T-cell–depleted allografts.41 These experi-
mental results impressively mirror our finding that the
highest frequency of increasing MC wasdetectable in those
cohorts that received T-cell–depleted stem cells. Thiscon-
firms that aT-cell depletion substantially reduces theallo-
reactivity of agraft, facilitates therecurrence of autologous
hematopoiesis, and allows theunderlying disease to newly
expand.42-44 Additional support for the GVL effect in pa-
tientswith ALL can befound in astudy from Locatelli et al
in which it wasreported that low-doseCSA reducestherisk
of relapse in children with acute leukemia receiving grafts
from human leukocyte antigen–identical siblings.45 Slavin
Fig 1. Kaplan-Meier analysis of event-free survival (EFS) for all study
patients (N 163). The 3-year EFS estimate was 54%.
Fig 2. Kaplan-Meier analysis of event free survival (EFS) according to chimer-
ism status. CC/LL-MC, complete chimerism/low-level mixed chimerism; de-
MC, decreasing mixed chimerism; in-MC, increasing mixed chimerism.
Fig 3. Kaplan-Meier analysis of event-
free survival (EFS) in patients with in-
creasing mixed chimerism (MC). Pa-
tients with increasing MC (in-MC) who
received additional therapy (A, n 31)
and patients with increasing MC who
did not receive additional treatment (B,
n 15).
Chimerism-Based Pre-Emptive Immunotherapy
www.jco.org 1701
Information downloaded from jco.ascopubs.org and provided by at Unibibliothek on February 12, 2012 from 141.2.86.220Copyright © 2004 American Society of Clinical Oncology. All rights reserved.
P. Bader et al.
J Clin Oncol 2004
Pre-emptive Immunotherapy
10
Author Numberof
patients
Diagnosis Interval ofinvestigatio
ns
Methods Relapses
Formakova
Haematologica 200354
AL, CML and MDS
children
weekly to +100;
monthly
STR
MC associated with rejection and relapse
Immunotherapy was possible
Gorczynska
BMT 200414
ALL, AML
children
weekly to+100;
monthly
STR
In-MC could beconverted by
immunotherapy to CC
Bader
JCO 2004163
ALL
children
weekly to +100;
monthly
STRMC associated with
relapse
Immunotherapy was possible in most patients
Horn
BMT 200820
AL
children
1,3,6,12 months;
In MC bi-weekly
STR
MC associated withrelapse
IT was not possible
Studies on Chimerism and
Intervention
11
• Immunotherapy (WD of immuno-suppression, DLI) is principally effective as pre-emptive treatment
• Chimerism can be used as surrogate marker for identifying patients at risk for impending relapse
However,Not in all patients!
Additional role for MRD?
Conclusion I
12
Impact of MRD prior to HSCTRetrospective Studies
Bader et al., Leukemia 2002
MRD „high“ n=17 pEFS 0.23
EFS
0,0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0
0 1 2 3 4 5 6 7 8 9 10Time [Years]
MRD negative n=14 pEFS 0.78
MRD „low“ n=10 pEFS 0.48
p=0,022
n=41
D-2 -3 -4 -5 -6
MW prior
„Semi quantitative“ Dot-Blot Hybridisierung
Knechtli et al., Blood 1998
13
Prospective evaluation
of MRD prior to HSCT
1999-2006
Inclusion criteria
Remission (≥ CR2)
Leukemia DNA from
diagnosis of relapse
BM Sample prior to
HSCT
P. Bader et al.
J Clin Oncol 2009
BFM ALL REZ GroupProspective pre-HSCT MRD Study
14
Probability curves of patients who
were MRD negative or positive by
flow cytometry or deep
sequencing. (A) Relapse risk by pre-
HCT NGS-MRD compared with MFC-
MRD status. (B) OS by pre-HCT NGS-
MRD compared with NGS-MRD status.
n=143
children and
adolescents with ALL
M.A. Pulsipher et al.
Blood 2015
MRD prior to HSCT: Flow versus
NGS
15
• Immunotherapy (WD of immunosuppression, DLI) is principally effective as pre-emptivetreatment
• Chimerism can be used as surrogate marker for identifying patients at risk for impending relapse
• MRD prior to transplant identifies patients at highest risk for relapse
Influence for current treatment and indication policy
Conclusion II
16
• Immunotherapy (WD of immunosuppression, DLI) is principally effective as pre-emptivetreatment
• Chimerism can be used as surrogate marker for identifying patients at risk for impending relapse
• MRD prior to transplant identifies patients at highest risk for relapse
• What adds analysis of post transplant MRD?
Conclusion III
17
day +30 +60 +90
gold: MRD negativegrey: MRD < 10E-4blue: MRD ≥ 10E-4
P. Bader et al.
J Clin Oncol 2015
Prognostic value of MRD I
Ped. ALL, n=113
18
Prognostic value of MRD II
day +180 +365
gold: MRD negativegrey: MRD < 10E-4blue: MRD ≥ 10E-4
P. Bader et al.
J Clin Oncol 2015
Ped. ALL, n=113
19
Author Numberof
patients
Diagnosis Investigation Methods Interpretation
Pochon
Br J Haematol. 2014
France
133ALL
children
MRD pre and post
Chimerism
Ig- TCR-RT-PCR
MRE strongly associated withrelapse prior and post.
Window for intervention
Bar
Leuk Res Treat 2014
FHRC
160ALL childrenand adults
MRD pre and post FlowMRD pre and post associtated of
relapse and inferior survival
Logan
BBMT 2014
UCSF/Stanford
29ALL
adultMRD pre and post
Flow MRD predicts relapse
Window for intervention
Bachanova
BBMT 2012
Minneapolis
86ALL childrenand adults
MRD pre
Cord transplantsFlow
MRD neg before transplant improves survival
Terwey
BBMT 2014
Berlin
101 ALL adultsMRD and
chimerism in subpopulation
Ig-TCR-RT-PCR;
STR
Chimerism in subpop predictable; MRD prior and post important; individual diagnosis possible
Balduzzi
Br J Haematol 201382
ALL
childrenMRD prior and post
Ig-TCR-RT-PCR;
MRD pre negative prognosticfactor; MRD post allows
prediction of relapse
Studies MRD Analysis in the setting
of HSCT 2012-2014
20
MRD Pre- and Post-HSCT
Lovisa et al.
Br J Haematol 2018
21
• MRD analysis is very important for stratification into different treatment arms prior to transplant >10-3 MRD prior to allogeneic SCT is independently related to
EFS and to CIR
Treatment modification to reduce MRD load prior to transplant is under investigation
• MRD assessment in BM post transplant is predictive for relapse and survival BM investigations are warranted and recommended on days 30,
60, 100, 200, 300, 365 and at 18 months
Patients who become/remain MRD positive >10-4, have an extremely high risk to relapse
MRD positive >10-3 leads to relapse!
Additional treatment in these patients seems to be warranted.
Final Conclusions
22Cancer immunotherapy
Tumor-antigen-specific T cell
MHC
Checkpoint blockade
anti-CTLA4
anti-PD1
anti-PDL1
T cell clones
CAR T cell
Tumor cell
TCR engineered T cell
BITE
Antibody-drug conjugated
Tumor antigen
Tumor antigen
DLI
NK cell
CIK cell
PDL 1
TCR
Dendritic cell
adapted: Maus et al. Blood, 2014
unspecificspecific
Treatment Options
23
Handgretinger et al.
Leukemia 2011
Nagorsen et al.
Leuk & Lymph 2009
T-cell Engaging Anti-CD19-Antibody Blinatumomab
24
Patient with c-ALL3rd relapse at day 200 after 1st allo-HSCT
-20 0 20 40 60
0
20
40
60
1.010-06
1.010-04
1.010-02
1.01000
1.01002
100 300
Days
cells p
er
nl
Leuko
Neutro
Lympho
MRD
Blinatumomab 2nd HSCT
25
CAR T-Cell Therapy
Lentiviral vector
T cell
CD19
Native TCR
Tumor cell
CTL019 cell
Dead tumor cell
Anti-CD19 CAR construct
26
S.L. Maude et al.
NEJM 2018
CTL019 - Tisagenlecleucel
27
CTL019 - Tisagenlecleucel
S.L. Maude et al.
NEJM 2018
28
CTL019 - Tisagenlecleucel
S.L. Maude et al.
NEJM 2018
29
Anti-CD3
IFNγIL-15
CIK
CIK
CIKCIK
CIKCIK
CIKCIK
Day 0 Day 21
IL-2
MNC
IL-2 IL-2 IL-2 IL-2
IFNγ
Anti-CD3
IL-2
Day 0
Day 1
Day 1every 3-4 days
Activation of monocytes, antigen cross-presentation
Mitogenic signals for T lymphocytes
T cell proliferation, survival and cytolytic effector function
Schmidt-Wolf et al. J Exp Med, 1991
Cytokine-induced killer cells
Cytokine-induced Killer Cells (CIK)
30
3 31
65
1 39
59
Day 7 Day 14
1 58
42
Day 21
CD3
CD56
Day 0
9 16
66
CD3+CD56+CD8+CD27+/-CD28-
Cytokine-induced killer cells
CIK
TCR
NCRs
Tumor
Granzyme
Perforin
MHC ICo-stimulation
Tumor peptide
TumorT cell receptor NKG2D receptor
a bCD3CD3
CD3 ζ
Tumor
CIKNKG2D
16xFITC CD3, DAPI, PE NKG2D
Pievani et al. Blood, 2011
Dual-functional capability
Phenotype and Function
31Cytokine-induced killer cells
0 3 6 9 12 18 24 30 360%
10%
50
100
150
0
500
1000
1500
2000
< 1x10-6
1x10-6
1x10-5
1x10-4
1x10-3
1x10-2
1x10-1
1x100
1x101
months post-transplant
#32
chimerism
MRD
T
T-NK
NK
cells/µl
recipientsignal
10 x106 CD3+/kg115
15
Molecular relapse
FFM: c-ALL, CR2, Allogeneic
HSCT (MUD)
32
Summary
• Prevention (and treatment) of relapse after allo-SCT
Options are increasingChances of cure after relapse are critical
Strategies to prevent relapse (MRD, chimerism and pre-emptive therapy!)
Leukemia targeting therapyEmerging: Antibodies
CAR T-cell therapy
LAA cell therapy
Cooperations
Halvard BönigGerman Red Cross Blood Donor Service Frankfurt/Main, Germany
Winfried S. WelsGeorg-Speyer-Haus, Frankfurt/Main, Germany
PhysiciansMichael MerkerShahrzad BakhtiarEva RettingerAndre WillaschAndrea JarischJan Sörensen
Graft Manipulation,Cell Therapeutics Sabine Huenecke Melanie BremmClaudia CappelVerena PfirrmannSibylle Wehner
Mesenchymal Stroma CellsZyrafete KuçiSelim Kuçi
CIK / T Cell TherapyEva RettingerVerena PfirrmannMichael MerkerLisa-Marie PfeffermannSarah OelsnerVida Meyer Molecular Biology
Andre WillaschChristlinde MauracherGitta NozadFariba SoltaniMiriam StaisHermann Kreyenberg
Pediatric Stem Cell Transplantation & Immunology: Peter Bader / Evelyn Ullrich / Thomas Klingebiel
Clinical Trial OfficeVerena PfirrmannBettina SteinmetzTina Homrighausen
OfficeKirsten Schäfer
NK cells / ExperimentalSara TognarelliJuliane WagnerJochen FrühKatja Thoma
Bio MathematicsEmilia Salzmann-Manrique
Participating Institutions Düsseldorf, Germany
Roland Meisel Florian Babor Friedhelm Schuster
Frankfurt/Main, Germany Hubert Serve Gesine Bug
Mainz, Germany Matthias Theobald Eva Wagner Hauptrock Beate
Heidelberg, Germany Johann Greil
34
Treatment strategies:Conventional DLI: Efficacy limited (Kolb et al. 1997)
Leukemia targeted immunotherapy Antibody treatment CD19, CD22, CD52
Cellular therapies: CAR T-cell therapy
CIK cell therapy
Checkpoint inhibition TKI, Dasatinib, JAK-inhibitors, Bortezomib,
Flt3-inhibitors, M-TOR inhibitors, aurora kinase inhibitors, Syk-inhibitors: limited data
Low-dose Chemo-Immunotherapy w/wo DLI
Second allogeneic SCT: EFS poor, 10-30%
Principal Considerations II
Immunotherapy with BlinatumomabWhat are the possibilities?
Peter Bader
SBTMO 2018 – ALL Satellite Symposium
“Role of MRD and Immunotherapy in Optimizing ALL Treatment Outcomes”
Rio de Janeiro, August 2nd, 2018
36
Objectives
• Refractory ALL
• Blinatumomab, Product, clinical development
• Blinatumomab in Children and Adults
TOWER Study; BLAST Study, AND RIALTO Study
Own data in 18 children
Present data from TOWER (AllHSCT in adults withR/R ALL from Phase 3
37
Poor Outcome for Patients with r/r
pB-ALLPediatric patients Adult patients
Standard pB-ALL
CR with frontline chemo 98-99% 85-90%
relapse 15-20% 30-50%
Long-term survival afterearly relapseslate relapses
25%50-60%
8%24%
r/r pB-ALL
Median OS with chemo only - 4.5-8.4 months
5y-median OS with chemo only - 7-10%
Median OS after chemo only - 10 months
Median OS after HSCT 7.4 months 5.8 months
New agents with reduced toxicity are needed to improve outcomes for patients with r/r pB-ALL
38
Bispecific T-Cell Engager:
Blinatumomab
Nagorsen et al. Leuk & Lymph 2009
Baeuerle P.A. et al. Cancer Res. 2009
Bargou R. et al. Science 2008
Topp M.S. et al. Lancet Oncol. 2015
Activation signals promote CTC proliferation
Klinger M. et al.
Blood 2012
Serial lysis of CD19+ B cells
Hoffmann P. et al.
Int J Cancer 2005
39Nagorsen et al. 2012
Blinatumomab – Mode of Action
40
Blinatumomab – Clinical Develpoment
Nagorsen et al. 2012
© Amgen Inc. All Rights Reserved.
A Phase 3, Randomized, Open Label Study Investigating the Efficacy of the BiTE Antibody
Blinatumomab Versus Standard of Care Chemotherapy in Adult Subjects With
Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL)
Study (TOWER) – NCT02013167
42
TOWER Study in Adult r/r pB-ALLS
cre
enin
g/P
re-p
hase
Safe
ty f
ollo
w-u
p
Blinatumomab
cIV infusion
4 weeks on
2 weeks off
2 cycles
SOC
chemotherapy
2 cycles
Consolidation3 cycles
Maintenance 12 months
Ran
do
miz
atio
n
© Amgen Inc. All Rights Reserved.
BLAST: A Confirmatory, Single-Arm, Phase 2 Study of Blinatumomab, a Bispecific T-Cell Engager (BiTE)
Antibody Construct, in Patients with Minimal Residual Disease B-Precursor Acute Lymphoblastic
Leukemia (ALL)
Study (BLAST) – NCT01207388
44
BLAST Study in Adult r/r pB-ALL, MRD-based
Scre
enin
g/P
re-p
hase
Safe
ty fo
llow
-up
Long-t
erm
follo
w-u
p
Blinatumomab15 μg/m2 cIV infusion
i.th. prophylaxis
4 weeks on2 weeks off
Up to 4 cycles
HSCT offered to patiens in CR
© Amgen Inc. All Rights Reserved.
Open-label, multicentre, expanded access study of blinatumomab* in paediatric and adolescent patients
with relapsed/refractory B-precursor ALL
Study 320 (RIALTO) – NCT02187354
*Blinatumomab is not licensed for use in paediatric patients in the EU
SC-EU-AMG103-00339-06.17
SC-DE-AMG103-00140
46
RIALTO Study in r/r pB-ALLS
cre
enin
g/P
re-p
hase
Safe
ty fo
llow
-up
Long-t
erm
follo
w-u
pBlinatumomab
cIV infusion
4 weeks on
2 weeks off
Up to 5 cycles
HSCT offered to patiens in CR
47
Key Eligibility CriteriaTOWER Study BLAST Study RIALTO Study
Age ≥18 y ≥ 18 y >28 d and <18 y
CD19+ pB-ALL with ≥5% blasts in BM
x x
CD19+ pB-ALL with <5% blasts in BMMRD ≥10E-4 (- ≥10E-3)
x
Ph negative x x x
2nd or later relapse, anyrlps. after HSCT, refractory disease1st relapse w remissonduration <12 months
xxxx
(x) xxx
Adequate liver function x x x
ECOG status ≤2 0 or 1
No prior HSCT x
48
Key Exclusion CriteriaTOWER Study BLAST Study RIALTO Study
Clinical relevant CNS pathology
x x x
Isolated extramedullarydisease
x x
Chemotherapy within 2 wk,Radiotherapy within 2-4 wk
x
x
x
x
x
x
Immunotherapy x
Immunosuppressionwithin 2 weeks
x x
Auto HSCT within 6 wkAllo HSCT within 12 wk
xx
xx
Grade 2-4 aGVHD,Active cGVHD
xx
xx
Abnormal liver orrenal function
xx
xx
49
Study EndpointsTOWER Study BLAST Study RIALTO Study
Primary endpoint: EfficacyOS
Primary endpoint: EfficacyMRD response after 1 cycle(MRD neg with sensitivity of at least 10E-4 by PCR in reference lab)
Primary endpoint: SafetyTreatment-emergent/related AEs
Secondary endpoint:EfficacyEFSRemission rate
SafetyIncidence and severity of AEs
Secondary endpoint:Efficacy (w/wo HSCT)RFSOSDuration of MRD response
SafetyIncidence and severity of AEs
Secondary endpoint:EfficacyCR within first 2 cyclesMRD neg. within first 2 cyclesRFSOSRate of allo-HSCT after CR
50
TOWER Study Blinatumomab vs. Chemo in Adult-ALL
Hagop Kantarjiann et al. NEJM 2017
Prospective 2:1 randomized trial: n=405
Blina: 271 Chemo: 134
Median OSBlina: 7.7 mo Chemo: 4.0 mo
CR/Cri (12 weeks): Blina: 36/44% Chemo: 16/25%
6 months EFS:Blina: 31% Chemo: 12%
Longer remission durationBlina: 7.3 mo Chemo: 4.6 mo
AES grade 3Blina: 87% Chemo: 92%
Treatment with blina resulted in longer OS
51
Zugmaier et al.
Blood 2015
n=36
BLAST Study Blinatumomab in MRD Positive Adult-ALL
52
BLAST Study Blinatumomab in MRD Positive Adult-ALL
Zugmaier et al.
Blood 2015
28% achieved an OS of 30 mo
Survival may be associatedwith MRD response
n=36
53
Results
Evaluable 113Median age 45 (18-76) yrsIn 2nd/later CR: 36%
MolCR: 78%
Median OS: 36.5 mo- Mol CR y/n: 38.9 vs 12.5 mo
Median RFS: 18.9 mo- Mol CR y/n: 23.6 vs 5.7 mo- 1st / later CR: 24.6 vs 11 mo
BLAST Study (Follow-up)Blinatumomab in MRD Positive Adult-ALL
Gökbuget et al.
Blood 2018
MRD response resulted in improved OS and RFS
54
RIALTO Study: Patient
Demographics and Baseline
Characteristics
Locatelli F, et al. ASCO 2017; Abstract 10530 and poster presentation.
Characteristic All patients (N=40)
Male, n (%) 19 (48)
Median (range) age, years 9 (1–17)
Age group, n (%)
1 month to <2 years
2 to <12 years
12 to <17 years
5 (13)
20 (50)
15 (38)
Prior relapses, n (%)
0 (primary refractory)
1
≥2
5 (13)
11 (28)
24 (60)
Prior allogeneic HSCT, n (%) 21 (53)
Bone marrow blasts (local), n (%)
<50%
≥50%
22 (55)
18 (45)
55
RIALTO Study: Response Within
first 2 Cycles
Locatelli F, et al. ASCO 2017; Abstract 10530 and poster presentation.
• Median number of cycles started and completed: 2 (range, 1−5)
All patients (N=40)
n/N1* % 95% CI
CR during the first two cycles
<50% blasts
≥50% blasts
t(17;19)
25/40
15/22
10/18
2/2
63
68
56
100
46–77
45–86
31–79
NA
MRD response during the first two cycles†
<50% blasts
≥50% blasts
t(17;19)
19/25
12/15
7/10
2/2
76
80
70
100
55–91
52–96
35–93
NA
HSCT realisation‡
Allogeneic HSCT after CR
Allogeneic HSCT without CR
10/25
3/14
40
21
21–61
5–51
56
RIALTO Study: Overall Survival
Locatelli F, et al. ASCO 2017; Abstract 10530 and poster presentation.
Censored at time of allogeneic HSCT N
Median OS, months
95% CI, months
Not censored 40 9.8 7.1–NE
Censored 40 8.3 5.4–9.8
181614121086420
0
0
1
0
1
0
1
0
3
1
7
1
12
4
12
4
15
7
16
8
17
9
22
12
30
18
33
25
33
30
37
37
39
39
40
40
0.0
0.2
0.4
0.6
0.8
1.0
Time (months)
Surv
ival pro
babili
ty
Number of subjects at risk:
Median follow-up: 11.8 months
Not censored Censored
Frankfurt Patients (N=18)
N (%) N (%)
Sex
Male
Female
14
4
(78)
(22)
Age
median [range]
13 years
[2 - 20]
Diagnosis
ALL
B-NHL
17
1
(94)
(6)
Number of SCTs before
treatment
0
1
2
7
10
1
(39)
(56)
(6)
Number of relapses before
treatment
1
2
3
4
9
6
2
1
(50)
(33)
(11)
(6)
Number of Blinatumomab
cycles
1
2
11
7
(61)
(39)
Duration of Blinatumomab
cycle
median [range]
28 days
[2-36]
Course after Blinatumomabmedian post treatment observation period: 1.6 years [25 days – 5.5 years]
Response to
BlinatumomabSCT after treatment
Total Yes (%) No (%)
CR (MRD+/-)8 6 (75) 2 (25)
NR10 7 (70) 3 (30)
Total18 13 (72) 5 (28)
Outcome in Patients with SCTs after
Blinatumomabmedian post SCT observation period: 2.5 years [83 days – 5.4 years]
Response to
BlinatumomabOutcome
Total CR (%) Relapse (%) TRM (%)
CR (MRD+/-)6 2 (33) 2 (33) 2 (33)
NR7 3 (43) 3 (43) 1 (14)
Total13 5 (39) 5 (39) 3 (23)
Outcome of patients without SCT (n=5)
Response to
BlinatumomabOutcome
Total CR (%) Lost to
follow-up
(%) Death (%)
CR (MRD+/-)2 2 (100) 0 (0) 0 (0)
NR3 0 (0) 2 (66) 1 (33)
Total5 2 (40) 2 (40) 1 (20)
Outcome of all patients (n=18)median post treatment observation period: 1.6 years [25 days – 5.5 years]
Response to
BlinatumomabOutcome
Total CR (%) Relapse (%) NRM (%) Lost
to FU
(%)
CR 8 4 (50) 2 (25) 2 (25) 0 (0)
NR10 3 (30) 4 (40) 1 (10) 2 (20)
Total18 7 (39) 6 (33) 3 (17) 2 (11)
Overall survival of patients since begin of
treatment with Blinatumomab
Time since begin of treatment (years)
Ove
rall s
urv
iva
l (%
)
0
20
40
60
80
100
2-y-p= 54.6%, 95%-CI: 32.4% - 92.1%
0 1 2 3 4 5 6
Overall survival of patients with CR vs. patients
with NR after treatment with Blinatumomab
CR includes CR MRD+
Time since end of treatment (years)
Ove
rall s
urv
iva
l (%
)
0
20
40
60
80
100
0 1 2 3 4 5 6
CR: 2-y-p= 71.4%, 95%-CI: 44.7% - 100%
NR: 2-y-p= 45.7%, 95%-CI: 20.3% - 100%
64
Summary• Allogeneic SCT remains the gold standard (highest risk, relapsed patients)
Children and adolescents with ALL
CR1: ultra high risk features, persistent MRD
CR2: - late relapses with pers. MRD- early, very early relapse
>CR2: all patients
Level of MRD prior to transplant is a major predictor for outcome
Antibody treatment Remission induction and improvement; reduce toxicity and clear MRD
post transplant
Adult Patients with r/r ALL
High risk for relapse and TRM irrespective of treatment
Patients with persistent remission after Blinatumomab
Efforts are focusing on minimizing the relapse risk by intensifying therapy upfront and by eradicating MRD using the new available immunotherapies e.g. Blinatumomab
Combining all these modalities (new therapies, conventional chemotherapy and HCT) is challenging.
Cooperations
Halvard BönigGerman Red Cross Blood Donor Service Frankfurt/Main, Germany
Winfried S. WelsGeorg-Speyer-Haus, Frankfurt/Main, Germany
PhysiciansMichael MerkerShahrzad BakhtiarEva RettingerAndre WillaschAndrea JarischJan Sörensen
Graft Manipulation,Cell Therapeutics Sabine Huenecke Melanie BremmClaudia CappelVerena PfirrmannSibylle Wehner
Mesenchymal Stroma CellsZyrafete KuçiSelim Kuçi
CIK / T Cell TherapyEva RettingerVerena PfirrmannMichael MerkerLisa-Marie PfeffermannSarah OelsnerVida Meyer Molecular Biology
Andre WillaschChristlinde MauracherGitta NozadFariba SoltaniMiriam StaisHermann Kreyenberg
Pediatric Stem Cell Transplantation & Immunology: Peter Bader / Evelyn Ullrich / Thomas Klingebiel
Clinical Trial OfficeVerena PfirrmannBettina SteinmetzTina Homrighausen
OfficeKirsten Schäfer
NK cells / ExperimentalSara TognarelliJuliane WagnerJochen FrühKatja Thoma
Bio MathematicsEmilia Salzmann-Manrique
Participating Institutions Düsseldorf, Germany
Roland Meisel Florian Babor Friedhelm Schuster
Frankfurt/Main, Germany Hubert Serve Gesine Bug
Mainz, Germany Matthias Theobald Eva Wagner Hauptrock Beate
Heidelberg, Germany Johann Greil
66
Can allogeneic HSCT in ALL be replaced by antibody therapy?
67
Principal Considerations Treatment of acute leukemiaMultimodal chemotherapy protocolsAdults Children and adolescents
Considerable improvement Leukemia free survival:
90% in children and adolescents with ALL
Indications for SCT CR1 only in high risk patients for ALL
Slow response, hypodiploidy, pers. MRD
CR2 Only high risk patients in children and adolescents with ALL
Early, very early relapses and slow MRD clearance in late relapses
CR3 All patients
68
Stem-Cell Transplantation in Children With Acute Lymphoblastic Leukemia: A Prospective
International Multicenter Trial Comparing Sibling Donors With Matched Unrelated Donors—
The ALL-SCT-BFM-2003 TrialChristina Peters, Martin Schrappe, Arend von Stackelberg, André Schrauder, Peter Bader, Wolfram Ebell,Peter Lang, Karl-Walter Sykora,
Johanna Schrum, Bernhard Kremens, Karoline Ehlert, Michael H. Albert,Roland Meisel, Susanne Matthes-Martin, Tayfun Gungor, Wolfgang
Holter, Brigitte Strahm, Bernd Gruhn,Ansgar Schulz, Wilhelm Woessmann, Ulrike Poetschger, Martin Zimmermann, and Thomas Klingebiel
C. Peters et al.
J Clin Oncol 2015
MSD: 71%
MUD: 69%
MSD: 3%
MUD: 10%MSD: 24%
MUD: 22%
MSD: 79%
MUD: 73%
69
Patient with ALL from 2005-2014n=99 in complete remission at the time of first transplantation
N % N %
Sex
Male
Female
60
39
61
39
Age
< 10 years
> 10 years
35
64
35
65
Remission
CR1
≥ CR2
54
45
55
45
Donor
MSD
MUD
Haploidentical
21
67
11
21
68
11
Phenotype
pB-ALL
T-ALL
bi-pheno ALL
82
12
5
83
12
5
Immunotherapy
(WD of CSA or DLI)
Yes
No
29
70
29
71
Frankfurt Experience
S. Bahktiar, submitted
70
n Events 4-y TRM P
━ 49 7 0.14 ±0.05 .129
━ 50 2 0.04±0.02
Ov
era
ll s
urv
iva
l
0 10 20 30 40 50 60
0.0
0.2
0.4
0.6
0.8
1.0
Outcome for ALL2005-2009 versus 2010-2014
months after SCT
TR
M
0 10 20 30 40 50 60
0.0
0.2
0.4
0.6
0.8
1.0
months after SCT
CIR
0 10 20 30 40 50 60
0.0
0.2
0.4
0.6
0.8
1.0
pE
FS
0 10 20 30 40 50 60
0.0
0.2
0.4
0.6
0.8
1.0
n Events 4-y EFS P
━ 49 18 0.63 ±0.07 .365
━ 50 10 0.77±0.06
2010-2014 (n=50) = 87%
2005-2009 (n=49) = 71%
2010-2014 (n=50) = 77%
2005-2009 (n=49) = 63%
n Events 4-y OS P
━ 49 14 0.71 ±0.06 .198
━ 50 6 0.87±0.05
n Events 4-y CIR P
━ 49 11 0.22 ±0.06 .958
━ 50 8 0.19±0.06
S. Bahktiar, submitted
71
CIBMTR Study. Period 2000-2011: Patients n=1458
2y: 50%
Segal et.al: Cancer 2017
72
THANK YOU!
Caso 1 – Anamnese e Diagnóstico
ID: HAKP, 43a, sexo feminino
QD/HPMA: internou em NOV/2015 com cansaço e dor torácica.AP: NEOPLASIA - CA PAPILIFERO DE TIRÓIDE 2008 – TTDA COM CIRURGIA E RADIOIODOTERAPIA ->hipotiroidismo e dislipidemia EXAME FÍSICO: descorada+
HEMOGRAMA: Hb 11.2 g/dl, leucócitos: 15,9 x109/L (neutro 4400 blastos 9200 = 58% e reaçãoleucoeritroblástica no esfregaço), Plaquetas 148 x109/LDHL: 6580 (normal até 618)
LÍQUOR: POSITIVO
MIELOGRAMA: infiltração por 90% de blastos linfóides (predomínio L1), alguns L2
IF: CD10+/CD19+/CD22+/CD25+fraco/CD34+/CD79a+/CD38+/CD58+/cyIgM negativo / CD20 negativoEGIL II = B COMUM
CARIÓTIPO/FISH: 46,XX der(11)t(1;11)(q12;q25). BCRABL E MLL/KMT2A - NEGATIVOS
BIOLOGIA MOLECULAR (FOUNDANTION): CREBBP (P879fs*49), CXCR4 (R338*-subclonal), YY1AP1(R93C)
Caso 1 – Tratamento e estratificação de risco
HD – LEUCEMIA LINFOBLASTICA AGUDA B (EGIL II - COMUM) – ALTO RISCO COM INFILTRAÇÃO SNC
NEOPLASIA SECUNDÁRIA A TERAPÊUTICA (RADIOIODO PRÉVIO ?)SEM DOADOR (APARENTADO E NÃO APARENTADO) FULLMATCH
TRATAMENTO – GRAALL 2005 (TROCADO RDT CRANIO POR 20 INTRATECAIS TRIPLAS)
- Refratária ao corticóide e pobre resposta precoce (> 1000 blastos após préfase e mieloD8 = 10% blastos por IF) MIGRA PARA O BRAÇO B
- DRM1 (IF) PÓS INDUÇÃO = 0.43% (POSITIVA)
- DRM2 (IF) PÓS CONSOLIDAÇÃO 1 < 0.01% (NEGATIVA)
– OPTADO POR TCPH HAPLO – DOADORA FILHA
Caso 1 – Transplante haploidêntico e seguimento
- MARÇO/16 – TCPH APARENTADO HAPLOIDÊNTICO (FILHA)
- FONTE MEDULA ESTIMULADA (GCSF) E DESERITROCITADA
- CONDICIONAMENTO DE INTENSIDADE REDUZIDA (FLU, MEL 140, THIOTEPA 5MG/KG+ CY PÓS), INCOMPATIBILIDADE ABO MAIOR
- D +45 APLASIA PURA SÉRIE VERMELHA
- D +150 PTLD EBV + MONOMÓRFICO AGRESSIVO EC: IVB – 4 RITUXIMAB + TROCA FKPOR SIROLIMUS REMISSÃO COMPLETA
- IMUNOSSUPRESSÃO – MMF ATÉ D+35 E RETIRADA COMPLETA DE SIROLIMUS – 9/10MESES
- SEM SINAIS DE GVHD AGUDO OU CRÔNICO
Caso 1 – Recidiva (Estudo medular de rotina)
- 1 ANO E 3 MESES - RECIDIVA IMUNOFENOTÍPICA MEDULA ÓSSEA COM SNC LIMPO• APESAR DE STR/QUIMERISMO LINF T > 98% E SEM IMUNOSSUPRESÃO• DRM 0,75%
- TRATAMENTO RESGATE 3 CICLOS BLINATUMOMABE + 1 MADIT (JUNHO/17) CICLO 1 – DRM PRÉ 0,75% DRM PÓS 0,01%CICLO 2 – DRM PRÉ 0,01% DRM PÓS NEGATIVA (<0,01%)
CICLO 3 – TÉRMINO EM OUTUBRO/17
…BUSCA DE NOVO DOADOR MAS SEM SUCESSO NAQUELE MOMENTO…
- NOVEMBRO/17 – INCIADO INFUSÃO DE LINFÓCITOS DO DOADOR (4 DOSES MENSAIS DE DLI)• 1a DLI: CD3 = 1 x 106/kg • 2a DLI: CD3 = 5 x 105/kg • 3a DLI: CD3 = 1 x 106/kg• 4a DLI: CD3 = 8 x 106/kg
FOLLOW UP (última avaliação): JUNHO/18 (1 ANO PÓS RECIDIVA)- Clínica: Alopécia (investigando possibilidade de manifestação de cGVHD)- Hemograma: Hb 13,6 / leuco 4100 (Neutro 2497, Ly 1119) / plaquetas 250 mil- Estudo de medula: DRM NEGATIVA- Hipogamaglobulinemia (pré blina IgG ~ 400 e pós ~ 200)
Caso 1 – DISCUSSÃO
Citogenética:- der(11) t(1;11) (q12;q25) – incomum em LLA e houve descrição desta translocação emalguns casos de neoplasias mielóides consideradas como NEOPLASIA SECUNDÁRIATERAPÊUTICA (RADIOIODO PRÉVIA ?)
Biologia Molecular:- CREBBP (P879fs*49) – resistência a corticoterapia (OBSERVADA NESTE CASO)
Condicionamento e fonte células e DLI (GvL):
- INTENSIDADE DO CONDICIONAMENTO – THIOTEPA 5MG/KG o uso de thiotepa10MG/KG OU TBI > 1000 cGy traria um desfecho melhor ?
- Impacto da DLI na recidiva e do GvL em LLA-B ?
...Seguimento: Quimerismo e DRM...
Obrigado!
YWHS, 22 anos, sexo masculino F2
Setembro 2015:
Em viagem para a França (Lille) iniciou quadro de febre e dores no
corpo, associado a fraqueza, cansaço e palidez. Realizou hemograma
que evidenciou pancitopenia. Feito mielograma com diagnóstico de
leucose aguda (LLA B), sendo encaminhado para nosso serviço para
tratamento.
Exame físico: hepatoesplenomegalia
Hemograma no diagnóstico:
HB: 4,8
Leuco: 10.800 (não temos o diferencial inicial na França)
Plaquetas: 15.000
Caso clínico
YWHS, 22 anos, sexo masculino F2
Setembro 2015:
Mielograma: 71% de células de tamanho pequeno a médio, alta
relação núcleo-citoplasmática, cromatina frouxa e citoplasma
escasso, compatíveis com BLASTOS LINFOIDES
YWHS, 22 anos, sexo masculino F2
Setembro 2015:
Mielograma: 71% de células de tamanho pequeno a médio, alta
relação núcleo-citoplasmática, cromatina frouxa e citoplasma
escasso, compatíveis com BLASTOS LINFOIDES
Cariótipo: 46,XY,t(14;19)(q32;q13.1) [10] / 46,XY [10]
Painel FISH LLA: sugestivo de: translocação do gene IGH em 60%
dos núcleos interfásicos analisados.
LCR negativo
Iniciado tratamento pelo protocolo GBTLI – 2009 – AR RL
D8 – 14% de blastos em SP (308 células)
D15 – Imunofenotipagem de MO: 7,7% de linfócitos B imaturos
anômalos que expressam CD34, CD45 (fraca expressão), CD20
(fraca expressão, CD22 (moderada expressão); correspondendo a
presença de Doença Residual de LLA-B nessa amostra
D 35 – MO com 2,4% blastos linfóides
Imunofenotipagem - 7,7% de células CD19 que expressam
CD34(fraca expressão), CD20(fraca expressão), CD38(fraca
expressão), CD58(fraca expressão) e negativas para CD10,
correspondendo a população linfóide B imatura anômala
falha de indução?
YWHS, 22 anos, sexo masculino F2
Outubro/Novembro 2015:
Reindução pelo protocolo COG AALL 0232 - consolidação
D14: MO em remissão morfológica e imunofenotípica
YWHS, 22 anos, sexo masculino F2
Dezembro 2015:
Identificado doador não aparentado 10/10 em registro internacional de
doadores de MO
Janeiro 2016
Transplante doador não-aparentado (10/10)
Fonte: medula óssea
Condicionamento: Irradiação corporal total 1200 cGy + Ciclofosfamida
120mg/Kg + ATG 5mg/Kg
Profilaxia da DECH: Ciclosporina A + MTX
Complicações: DECH pele grau I; reativação CMV
Recuperação neutrofílica: D+18
Reavaliações medulares programadas
D+ 60: DRM negativa; quimerismo 100%
D+ 100: DRM negativa; quimerismo 100%
D+ 180: DRM negativa; quimerismo 100%
D+ 360: DRM negativa; quimerismo 100%
YWHS, 22 anos, sexo masculino F2
Março 2017 (14 meses pós transplante):
Internação por febre + perda de peso + plaquetopenia
Massa esfenoidal + captação arco costal (PET CT: SUV 10,3)
YWHS, 22 anos, sexo masculino F2
Março 2017 (14 meses pós transplante):
Mielograma: 68,0% de blastos linfoides
Imunofenotipagem: 76,4% células anômalas: CD10 (fraca expressão),
CD19 (moderada expressão), CD22 (moderada expressão), CD34 (forte
expressão), CD123 (moderada expressão), cyCD79a (fraca expressão), cyIgM
(moderada expressão); sendo compatível com Leucemia Linfoblástica B /
Leucemia Linfoide pré-B
Citogenética com evolução clonal
46,Y,t(X;12)(q24;q13),t(10;16)(q26;p11.2),t(14;19)(q32;q13.1)[7]
Anatomo-patológico lesão esfenoidal: infiltração de mucosa respiratória por
leucemia linfoblástica aguda de imunofenotipo b
Considerado SNC positivo
Tratamento – Protocolo HAM: ARAC 3gm2 12/12h d1-d3-d5 +
mitoxantrone 20mg/m2 d1-d3
Reavaliação Abril 2017 (14 dias após término)
Mielograma: 76,0% blastos linfoides.
Imunofenotipagem: 66,4% blastos, há expressão antigênica
positiva e significativa de CD19(moderada expressão),
CD22(moderada expressão)
YWHS, 22 anos, sexo masculino F2
Abril 2017:
Tratamento – protocolo TACL (sem antracíclicos): vincristina +
bortezomib + dexa + PEG-asparaginase
Asparaginase suspensa no D22 por pancreatite
Reavaliação Maio 2017
Mielograma: hipocelular sem blastos
Imunofenotipagem: 0,5% de precursores linfoides B anômalas positivos para
CD19, CD22 (fraca a moderada expressão), CD34, CD45 (fraca a moderada
expressão) e negativos para CD10, CD20, CD38 e CD58, correspondendo a
doença residual mínima positiva para LLA-B, nesta amostra.
22/04/2017
Aparecimento de lesões de pele em coxa D e MSD
Aumento da lesão expansiva sólida em parte do seio esfenoidal direito
Biópsia de pele e da massa em esfenóide: mucormicose
YWHS, 22 anos, sexo masculino F2
Maio 2017:
Blinatumomabe #1 (22/05 a 19/06)
Reavaliação (20/06):
Mielograma: normocelular sem blastos.
Imunofenotipagem: 0,05% de precursores B anômalos que expressam CD10,
CD22, CD34, CD38 (forte expressão), CD45 (fraca expressão), CD81 e HLA-
DR. Essas células são negativas para CD19, CD20, CD58 e CD123.
Julho 2017:
Blinatumomabe #2 (04/07 a 31/07)
Reavaliação (14/08):
Mielograma: normocelular sem blastos.
Imunofenotipagem: 0,02% de células linfóides B imaturas anômalas que
expressam CD22, CD10, CD34, CD45 (fraca expressão) e CD38. Esta
população é negativa para CD19, CD20 e CD58.
Agosto 2017 – em programação de 2º transplante
Blinatumomabe #3 (17/08 a 25/08)
29/08: DRM negativa
YWHS, 22 anos, sexo masculino F
2
Setembro 2017
Transplante doador não-aparentado (10/10) – doador diferente do
primeiro transplante
Fonte: sangue periférico
Condicionamento: Bussulfano (AUC 5000) + Fludarabina (150) +
Thiotepa (10) + ATG (5)
Profilaxia da DECH: Ciclosporina A + MTX
Profilaxia secundária de reativação de infecção fúngica: biterapia com
anfotericina lipossomal + posaconazol + transfusão de granulócitos
Complicações: DECH aguda grau II (TGI 2), com boa resposta a
corticoterapia; colite por chlostridium, reativação CMV
Recuperação neutrofílica: D+18
Desmame do CE até D+90, desmame de CsA até D+150
YWHS, 22 anos, sexo masculino F2
Junho 2018
Atualmente bem, sem intercorrências clínicas
Voltou a faculdade e ao trabalho
Em programação de cirurgia de catarata
Reavaliações medulares programadas
D+ 60: DRM negativa; quimerismo 100%
D+ 100: DRM negativa; quimerismo 100%
D+ 180: DRM negativa; quimerismo 100%